The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Clinical Features and Outcomes of Serotype 19A Invasive Pneumococcal Disease in Calgary, Alberta

BACKGROUND: Streptoccocus pneumoniae serotype 19A (ST19A) became an important cause of invasive pneumococcal disease (IPD) after the introduction of the conjugate vaccine

Covid-19 Vaccine Confidence, Concerns, and Uptake in Children Aged 5 and Older in Calgary, Alberta: a Longitudinal Cohort Study

OBJECTIVES: Beginning early in the pandemic, there was a worldwide effort to develop effective vaccines against the SARS-CoV-2 virus. Before and after the approval and implementation of vaccines, there were concerns about their need as well as their safety and rapid development. We explored child demographic characteristics and parental concerns to identify factors associated with the decision to vaccinate. METHODS: A cohort of 1035 children from Calgary was assembled in 2020 to participate in 5 visits every 6 months for survey completion and blood sampling for SARS-CoV-2 antibodies. Visits 1 to 2 occurred before approval of vaccines for children; Visits 3 to 5 occurred after vaccine approval for different age groups. We described vaccine concerns and utilized logistic regression to examine factors associated with the decision to vaccinate in children ≥5 years of age. RESULTS: Children ≥12 years of age, of non-white or non-black ethnicity, and who had received previous influenza vaccines had higher odds of being vaccinated against SARS-CoV-2. Children with previous SARS-CoV-2 infection had lower odds of being vaccinated. The most common concerns in early 2021 were about vaccine safety. By summer 2022, the most common concern was a belief that vaccines were not necessary. Through the study 88% of children were vaccinated. CONCLUSIONS: Age, ethnicity, previous infections, and vaccine attitudes were associated with parental decision to vaccinate against SARS-CoV-2. For children who remained unvaccinated, parents continued to have safety concerns and questioned the necessity of the vaccine. Complacency about the need for vaccination may be more challenging to address and overcome than concerns about safety alone

Structure of an Enzyme-Derived Phosphoprotein Recognition Domain

Membrane Associated Guanylate Kinases (MAGUKs) contain a protein interaction domain (GKdom) derived from the enzyme Guanylate Kinase (GKenz). Here we show that GKdom from the MAGUK Discs large (Dlg) is a phosphoprotein recognition domain, specifically recognizing the phosphorylated form of the mitotic spindle orientation protein Partner of Inscuteable (Pins). We determined the structure of the Dlg-Pins complex to understand the dramatic transition from nucleotide kinase to phosphoprotein recognition domain. The structure reveals that the region of the GKdom that once served as the GMP binding domain (GBD) has been co-opted for protein interaction. Pins makes significantly more contact with the GBD than does GMP, but primarily with residues that are conserved between enzyme and domain revealing the versatility of the GBD as a platform for nucleotide and protein interactions. Mutational analysis reveals that the GBD is also used to bind the GK ligand MAP1a, suggesting that this is a common mode of MAGUK complex assembly. The GKenz undergoes a dramatic closing reaction upon GMP binding but the protein-bound GKdom remains in the ‘open’ conformation indicating that the dramatic conformational change has been lost in the conversion from nucleotide kinase to phosphoprotein recognition domain

Efficient Strict-Binning Particle-in-Cell Algorithm for Multi-Core SIMD Processors

International audienceParticle-in-Cell (PIC) codes are widely used for plasma simulations. On recent multi-core hardware, performance of these codes is often limited by memory bandwidth. We describe a multi-core PIC algorithm that achieves close-to-minimal number of memory transfers with the main memory, while at the same time exploiting SIMD instructions for numerical computations and exhibiting a high degree of OpenMP-level parallelism. Our algorithm keeps particles sorted by cell at every time step, and represents particles from a same cell using a linked list of fixed-capacity arrays, called chunks. Chunks support either sequential or atomic insertions, the latter being used to handle fast-moving particles. To validate our code, called Pic-Vert, we consider a 3d electrostatic Landau-damping simulation as well as a 2d3v transverse instability of magnetized electron holes. Performance results on a 24-core Intel Sky-lake hardware confirm the effectiveness of our algorithm, in particular its high throughput and its ability to cope with fast moving particles

Mechanisms for the Evolution of a Derived Function in the Ancestral Glucocorticoid Receptor

Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs—reduced sensitivity to all hormones and increased selectivity for glucocorticoids—are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR–MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution

Serotype distribution of remaining pneumococcal meningitis in the mature PCV10/13 period: Findings from the PSERENADE Project

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites (N = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites (N = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed

Invasive Pneumococcal Disease in Calgary During the Sars-CoV-2 Pandemic 2020

During the Sars-CoV-2 pandemic in 2020, many countries shut down schools and businesses in an effort to slow transmission of the virus. As some businesses reopened, increased public health protocols, mask wearing, hand sanitizer, and personal protective equipment use remained. The shut down and public health restrictions for person-to-person interaction, resulted in a decline of other transmissible diseases as well as Sars-CoV-2. In Calgary, the incidence of invasive disease due to Streptococcus pneumoniae declined to much lower levels than would be expected in early spring and remained low until December 2020. This decline occurred despite no changes in vaccine use and uptake.Othe